Dihydroanthracene compounds



United States Patent Q 3,177,209 DIHYDROANTHRACENE COMPOUNDS Torkil O.Hohn, Copenhagen, Denmark, assignor to Kefalas A/S, Copenhagen-Valby,Denmark No Drawing. Filed Sept. 7,1961, Ser. No. 136,427 Claimspriority, application Great Britain, Sept. 16, 1960, 32,011/60; Feb. 17,1961, 5,893/ 61 22 Claims. (Cl. 260-240) The present invention relatesto novel dihydroanthracene compounds of the general formula:

wherein R and R each represents a lower-alkyl group, R and R 4each'represents a lower-alkyl group, or one may represent a lower-alkylgroup and the other a benzyl group, or R and R taken together withthe'nitrogen atom represent the radical of a heterocyclic amine having asaturated five-membered or six-membered ring, X represents hydrogen,halogen, a lower-alkyl group, or a lower-alkyloxy group, and Yrepreesnts hydrogen or halogen, as well as acid addition salts thereof.

It is an object of the preesnt invention to provide noveldihydroanthracene compounds, a method of making the same, a method forthe alleviation, palliation, mitigation, or inhibition of themanifestations of certain physiological-psychological abnormalities ofhuman beings therewith, and pharmaceutical compositions'comprising suchnovel dihydroanthracene compounds as active ingredient. Other objectswill be apparent to one skilled in the art and still other objects willbecome apparent hereinafter.

The compounds of Formula I and the acid addition salts thereof areuseful therapeutics and possess valuable pharmacodynamic properties. Inanimal experiments the compounds show sedative effects. They furtherexhibit a mydriatic and anticholinergic elfect and potentiate the effectof adrenaline, noradrenaline andbarbiturates. In addition, some of thecompounds of Formula I show local anesthetic effects. In clinical trialsthe compounds of Formula I, and especially9-gamma-dimethylaminopropylidene-IO,lO-dimethyl 9,10 dihydroanthracene,have been found effective in the treatment of psychotic patients, forexample patients sulfering from depressions.

When the compounds of Formula I are asymmetrically substituted in thephenyl rings, they may exist as two geometric isomers of the cis-transtype, which isomers although similar are not identical with respect totheir pharmacodynamic properties. The isomers may be sep aratedaccording to procedure conventional in the art.

The compounds of Formula I and the acid addition salts thereof may beadministered both orally and parenterally, for example in the form oftablets, capsules, powders, syrups or solutions for injection.

The invention moreover relates to a method for the preparation ofcompounds of Formula I, whereby a 10,

"ice

lO-diloweralkyl-anthrone compound of the followin formula:

wherein all" of the symbols havethe values previously assigned, isdehydrated, and theresulting compound of Formula I isolated as the freebase or in" the form of an acid addition salt and, in the. event saidcompound of Formula I or said addition salt thereof is a mixture ofisomers, individual isomers thereof isolated, if desired, by procedurealready known'for the separation and isolation. of such isomers.

The Grignard reaction step according tothe invention may conveniently becarried out according to conventional procedure for such reactions in aninert solvent such as diethyl-ether, di-n-butyl-ether, tetrahydrofuran,or the like.

The dehydration step according to the invention may be elfected by meansof agents ordinarily used for such puropse, e.g., inorganic acidhalidessuch as phosphorus oxychloride and thionyl chloride, hydrogen halides,sulphuric acid, iodine in benzene, potassium bisulphate, zinc chloride,and the like, and it has been found very convenient to carry out saiddehydration by reacting compounds of Formula III, which are hithertounknown, with a hydrogen halide, e. g., hydrogen. chloride, in an inertorganic solvent such as chloroform, benzene, toluene or the like. I

The acid addition salts of the novel compounds of Formula I arepreferably salts of pharmacologically acceptable acids such as mineralacids, for example, bydrochloric acid, hydrobromic acid, phosphoricacid, sulphuric acid, and the like, and organic acids such as aceticacid, tartaric acid, maleic acid, citric acid, ethanesulphonic acid andthe like.

(III) In'the foregoing .Formula I and elsewhere herein, the

.terms loWer-alkyl and lower alkyloxy refer to alkyl or alkyloxyradicals containing up to and including eight carbon atoms, andpreferably no more than three carbon atoms,

which radicals may have either straight or branchedchain structure, forexample methyl, ethyl, propyl, isopropyl, butyl, isobutyl, .amyl, hexyl,heptyl, 'octyl, methoxy,' ethoxy, propoxy, butoxy, amyloxy, hexoxy,heptoxy,

or the like.

As representative examples of radicals in' which R and R together withthe nitrogen atom in Formula I represent the radical of a heterocyclicamine having a saturated five-membered or six-membered'ring may bementioned the pyrrolidine, piperidine,morpholine, thiamorpholine, N-lowenalkylpiperazine, e.g.,. -methylpiperazine, or such radicalscontaining from one to four or even more C-loWer-alkyl, e.g., C-methyl,substituents, .e.g-.,'- tetramethylpyrrolidine,and like radicals.

The starting 10,10-dilower alkyl-anthrone compounds of Formula II arepreferably such compounds wherein X and Y'are hydrogen and, inthe'Grignard reagent, R

and R are preferably methyl groups, not only from the a; Example 4.-9gammadimethylaminopropylidene 3-chloro-10,lO-dimethyl-9,10-dihydroanthracene and its hydrochloride WhenExample 1 is carriedout using 44 grams (0.171

mole) of ,3'chloro-10,l0-dimethylanthrone instead of 10,l-dimethylanthrone, the hydrochloride of9-gamma-dimethylaminopropylidene, 3-chloro-l0, l 0-dimethyl-9 ,10-dihydroanthracene is obtained. M.P. 213-216 degrees centigrade. g

Example 5.-9 gamr na N-piperidinopropyHelene-1 0,10- dimethyl-9,JO-dihydroanthracene and its hydrochloride When Example l'is carriedout using 0.2 mole of N- gamma-piperidinopropylmagnesium chlorideinstead of dimethylaminopropylmagnesium. chloride, the; hydro chlorideof 9-gamma Npiperidinopropylidene-l0,lO-dimethy1+9,lilrdihydroanthracene isobtained: M.PL- 266 269 degrees.centigrade.v ,Yield 35 grams.

standpoint of pharmacological importance and availability of thesestarting materials, but also from the standpoint ofiease of operationand smoothness of reaction.

The following examples are given by way of illustration only and arenotbe construed as limiting.

Example I .-9.-gamma-'dim ethylaminopropylidene-l 0,1 0dimethyl-9,]0-dihydroanfhracene and its hydrochloride To 36 grams (0.171mole) of 10,10-dimethylanthrone.

dissolved in 300 milliliters of ether is added a dispersion of 0.3 nioleof dimethylaminopropylmagnesium chloride in 400 milliliters of ether;The reaction .mixture is stirred for one hour under gentle reflux.Thereafter 100 milliliters of water are added drop-wise, and 'theetherphase is separated. and evaporated to dryness. The residue, consistingmainly of 10,lO-dimethylQ-gamma-dh methylaminopropyl-9-anthrol isdissolved in 100 milliliters of chloroform and a stream of 'dry'hydrogenchloride introduced into the solution. This introduction is can.

* .tinued, .while refluxing for half; an hour. on a steam bath,

whereupon the solution is evaporated'to dryness in vacuo. The residue isrecrystallized from acetone, and the crystals of the hydrochloride of9-gamma-diinethylaminopropylidene.-10,10-dimethyl-9,l0-dihydroanthraceneformed are separated from solvent by vacuum filtration anddried. M.P.245-248 degrees centrigrade.

Example 2.+--9-gamma-dimethylaminopropylidene-IOJ0-dz'ethyl-QJO-dihydroa thracene and its hydrochloride When Example 1iscarriedout using 42.5 grams (0.171 mole) of 10,10-diethylanthroneinsteadof 10,10-dirnethylanthrone, ithe hydrochloride of9-gamma-dimethylaminopropylidene-10,10-diethyl-9,l'mdihydroanthracene isob-. tained; M.P. 176-179 degrees oentigrade.-

Example 3.-9 gamma dimethylaminopropylidene 2-,.

. chlofo-I0,l0=dimethyl-9,IO-dihydmanthracene, its. geometric isomers,and hydrochlorides thereof 7 When Example .1 is carried out using. 44grams (0.171

mole) of 2-ch1oro-10,IO-dirhethylanthrone (M.P.. 95-.

100 C.) instead of .10,l0-dimethylanthrone, the hydro-..

chloride of one of the geometricisomers of9-gammadimethylaminopropylidene-2-.chloro-10, 10,-diniethyl-9,

dihydroanthracene is isolated in a yield of twenty grams as I awhitecrystalline powder. melting at'255-257 degrees centigrade. r I

The acetone .mother. liquor from thecrystallization of this isomer.isjevaporatedto drynessQthe residue recrystal- .lixed' from methanol,and the crystals-of the other geometric isomer. are separated by vacuum.filtration. and

dried. M.P. 216-218 degrees centigrade. Yield ten grams.

dry hydrogen chloride .used .ingExample -1.

ample, by employing hydrobromic, tartaric, malonic,,

Example 6.Other 9egamma-dimethylaminopropylidene- 2- and-3-ha'l0-10,10-dimethyl 9,1O-dihyidroanthracenes and salts thereof f Inthe same manner; as. given in Example 1, the compounds 2- and3-br0mo-9-gamma-dimethylaminopropylidene-10,l0-dimethyl-9,lfldihydroanthracene and 2-1 and 3fiuoro-9-gamma-dimethylaminopropylidene-l0,10-dimethyl-9,IO-dihydrbanthraceneare prepared, by respec- [prepared starting from the. 2,7.-dichloro-10,l05dimethyl- V anthrone and dimethylarninopropylmagnesium chloride;

Example 7.Other 9,10-dihydroanthrac'enes and salts thereof In the samemanner as: given in Example. l, the com.-

pounds 9-. (gamma N pyrrolidinopropylidene) -l 0,l0-dimethyl-9,IO-dihydroanthracene and 9-'[-gamma N-'methyl-Npiperazino.) '-propylidene]'- 10,lO-dimethyl-9,lO-dihyd-roanthracene areprepared, by respectively employing as startingmaterials forreactionwiththe 10,10-dimethylanthrone, the compoundsN-gamma-pyrrolidinopropylmagnesium chloride and gamma-(N'-n1ethyl Npiper azino)-propylmagnesimn chloride.

1, using for example hydrochloric, hydrobrornic, sulphuric, acetic,nitric, phosphoric, lactic, citric, tartaric, 7

malonic, oxalic, methane or ethane-sulphonic, or like acids.

Example 8.- 0ther acid addition salis' In the-same manner as given inExample 1, other acid addition-salts of the compounds of the foregoingexamples are prepared by employingother acids in place, of the For; ex-

oxalic, methane or ethanesulphonic, or' like acids, the correspondingacidaddition salts of thefree basic amines of these examplesiareproduced.

The compounds of Formula I and the. acidiaddition salts thereof may beadministered to animals including human beings both orally andparenterally, and may be used-forexample in the form oftablets,,capsules, powders,

syrups or in the form of the usual. sterile. solutions for injection;Results, upon administration to human beings have been very gratifying.

Mostconveniently the-compounds of FormulaJ are administered orally inunit dosage form such as tablets In "exactly the same Their acidaddition salts are produced and isolated in the manner of Example orcapsules, each dosage unitcontaining a non-toxic acid addition salt ofone of the said compounds in an amount of from 5 to 100 mg. calculatedas the free amine, the total daily dosage usually ranging from about mg.to 1500 mg. The exact individual dosages. as well as daily dosages in aparticular case will of course be determined according to establishedmedical principles under the direction of a physician.

When preparing tablets, the active ingredient is for the most part mixedwith ordinary tablet adjuvants such as corn starch, potato starch,talcum, magnesium stearate, gelatine, lactose, gums, or the like. Asuitable formula for a tablet containing 25 mg.9-gamma-dimethylaminopropylidene 10,10 dimethyl 9,10 dihydroanthracene(called N 7001 for short) in the form of its hydrochloride is asfollows:

Any other pharmaceutical tableting adjuvants may be used provided thatthey are compatible with the active ingredient, and additionalcompositions, dosage forms, individual dosages and daily dosages may bethe same as or approximate those presently in use for the drugimipramine.

As previously stated, when isolating the compounds of Formula I in theform of an acid addition salt, the acid is preferably selected so as tocontain an anion which is non-toxic and pharmacologically accepable, atleast in usual therapeutic dosages. Representative salts which areincluded in this preferred group are the hydrochlorides, hydrobromides,sulphates, acetates, phosphates, nitrates, methanesulphonates,ethanesulphonates, lactates, citrates, tartrates or bitartrates, andmaleates of the amines of Formula 1. Other acids are likewise suitableand may be employed if desired. For example, furnaric, benzoic,ascorbic, succinic, salicylic, bismethylene-salicylic, propionic,gluconic, malic, malonic, mandelic, cinnamic, citraconic, stearic,palmitic, itaconic, glycolic, benzenesulphonic and sulpharnic acids mayalso be employed as acid addition salt-forming acids. When'it is desiredto isolate a compound of the invention in the form of the free base,this may be done according to conventional procedure, as by dissolvingthe isolated or unisolated salt in water, treating with a suitablealkaline material, extracting the liberated free base with a suitableorganic solvent, drying the extract and evaporating to dryness orfractionally distilling to eflfect isolation of the free basic amine.

It is to be understood that the invention is not limited to the exactdetails of operation or exact compounds or compositions shown anddescribed, as obvious m0difications and equivalents will be, apparent toone skilled in the art, and the invention is therefore to be limitedonly by the scope of the appended claims.

I claim:

1. A compound selected from the class consisting of (l) aminopropylidene9,10-dihydroanthracenes of the,

in which each of R and R is a lower-alkyl group, X is selected from thegroup consisting of hydrogen, halogen,

. 6 lower-alkyl and lower-alkyloxy, Y is selected from th groupconsisting of hydrogen and halogen, and.

2. 9 -gamma dilower alkylaminopropylidene 10,10-

dilower-a1kyl-9, 1 O-dihydroanthracene.

3. 9 gamma dilower alkylaminopropylidene 10,10-

dilower-alkyl-9,IO-dihydroanthracene acid addition salts.

4. 9 gamma-dilower-alkylaminopropylidene-10,10-dilower-alkyl-9,IO-dihydroanthracene hydrochloride.

5. 9gamma-dimethylaminopropylidene-10,IO-dimethyl-9,10-dihydroanthracene.

6. 9gamma-dimethylaminopropylidene-10,IO-dimethyl-9,10-dihydroanthraceneacid addition salts.

7. 9gamma-dimethylaminopropylidene-10,10-dimethy1-9,l0-dihydroanthracenehydrochloride.

8. 9-gamma-dilower-alkylaminopropylidene 2 halo-10,10-dimethyl-9,IO-dihydroanthracene acid addition salts.

9. 9-gamma-dilower-alkylaminopropylidene 3 halo-10,l0-dimethyl-9,IO-dihydroanthracene non-toxic acid addition salts.

10. 9gamma-N-piperidinopropylidene-10,10-dimethy1-9,IO-dihydroanthracene acidaddition salts.

11. 9-gamma diloweralkylaminopropylidene-Z-chloro-lO,10-dimethy1-9,lO-dihydroanthracenenon-toxic acid addition salts.

12. 9gamma-dilower-alkylaminopropylidene-3-chloro-10,10-dirnethyl-9,lO-dihydroanthracenenon-toxic acid addition salts. p

13. 9 gamma-dimethylaminopropylidene 2 chloro-10,10-dimethyl-9,IO-dihydroanthracene non-toxic acid addition salts.

14. 9 gamma-dimethylaminopropylidene 3 chloro-10,10-dimethyl-9,IO-dihydroanthracene non-toxic acid addition salts.

15. An anthrol compound of the formula:

in which each of R and R is a lower-alkyl group, X is selectedfrom thegroup consisting of hydrogen, halogen, lower-alkyl and lower-alkyloxy, Yis selected from the group consisting of hydrogen and halogen, and

is selected from the group consisting of di-lower-alkylamino,benzyl-lower-alkylamino, the radical of a heterocyclic amine, having asaturated five-membered ring, and the radical of a heterocyclic aminehaving a saturated six-membered ring, said heterocyclic amines beingselected from the group consisting of pyrrolidine, piperidine,morpholine, thiamorpholine, N -loweralkylpiperazine, and C- lower-alkylderivatives of the foregoing.

16. 9 gamma dilower alkylaminopropyl-10,10-di- 1oWer-alkyl-anthrol-9.

17. 9-gamrna-dimethylaminopropyl 10,10 dimethylanthrol-9.

. dimethyl-anthro1-9.

2 1. 9 gamma-dilower-alkylaminopropyl 3 chloro-10,1.0-dimethy1-antl1rO1-9.

22. 9"- gamma-N-piperidinopropyl-10,10-dimethy19,10-

anthro1-9.

- References Cited by the'Examiner; UNITED STATES PATENTS 1 2 2,404,2197/46 Cusic 260-293 2,891,957 6/59 Allen. et a1 260-240 X 2,907,761 10/59Benton 260-240 2,951,082 8/60 Sprague et a1. 260-240 X r 2,955,073 10/60De Beer 167-65 2,996,545 8/61 Bottoms 260-5703 3,035,977 5/62 Abood' -Q.167-65 3,073,847 1/63 v Doebel 6t al. 260-240 X.

FOREIGN PATENTS 99,624 5/60 Czechoslovakia. 1,109,166 6/61- Germany.

OTHER REFERENCES 1 Barnett et a1.-:,.Ber. d. Dent. Chem. Ges., vol. 62,pages 30673068 and 3072-4 (1929). v

Bonvicino et 211.; J. OrgLChem v01. 26, pages 2383 to 2392 (July 1961).'

Curtin et.a1.: J. of the Am. Chem. 500., vol. 81, pages 4719-4728(September 5, 1959).

My' chajlyszyn et aL: Collection of Czech. Chemlcdm munications, vol.24, page'3955 (1959). 1

. IRVING MARCUS, Primarj Examiner. JOHN D. RANDOLPH, Examiner;

1. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF (1) AMINOPROPYLIDENE9, 10-DIHYDROANTHRACENES OF THE FORMULA: